Verifying the Theory of Climate Affecting Lethality of COVID-19 by an Analysis in Two Climatic Zones of Chile

Introduction: The study of seasonal influences on the COVID-19 pandemic can take advantage of the unique position of Chile and its different climatic profiles in the north-south extension. The purpose is to verify the influence of seasonal climate changes on the COVID-19 in the temperate and sub-arctic areas of Chile. Methods: We monitored the evolution of CFR in temperate versus sub-boreal regions, reporting from the John Hopkins University COVID-19 Center on the CFR in each province in midwinter, spring, and early summer. Results: CFR worsened from mid-winter to mid-spring in the temperate zone of Chile, while in the sub-boreal area the CFR improves in the same period, (Kruskal Wallis Test, p=0.004). In the temperate zone after the increase in late winter-early spring, CRF tends to stabilize;on the contrary in the sub-boreal zone, there is a more marked tendency to worsen the CFR at the same time (Kruskal Wallis Test, p=0.010). The temperate zone of Chile shows a CFR increasing until spring-like temperate Europe, unlike Europe CFR does not decrease in summer, but the mean minimum temperature in temperate Chile is lower in summer than in temperate Europe. In Patagonian, CFR remains stable or drops from winter to spring but increases in early summer. Conclusion: The temperate and sub-boreal zones of Chile have a markedly different CFR variation profile during the COVID-19 pandemic.

Strong ACE-2 expression in the choroidal vessels: do high choroid plexuses serve as a gateway for SARS-CoV-2 infection on the human brain?

OBJECTIVE: Previous studies have confirmed the key mechanism by which SARS-CoV-2 enters human cells. It is well established that ACE2 is the receptor that can mark the beginning of the infection. In light of this, the organs that express higher levels of ACE2 are generally considered at higher risk, while those with lower levels should be somehow more protected. This - if related to the scarcity of ace2-expressing cells in the brain - seems to contrast with the presence of a variety of neurological symptoms that follow infection with ace2.  The aim of this work was to analyze ACE2 expression in the human brain, focusing on the choroid plexuses. PATIENTS AND METHODS: Twenty brain samples were obtained at autopsy from ten human fetuses and from ten adult subjects. All samples were selected to contain the choroid plexus. Specimens were fixed in 10% formalin, routinely processed and paraffin embedded. 5-micron sections were stained with Hematoxylin and Eosin (H&E) and immunostained with a commercial anti-human ACE2 rabbit monoclonal antibody at 1:100 dilution. RESULTS: We analyzed 20 samples by immunohistochemistry, and we noted that, as far as fetal samples are concerned, a strong reactivity for ACE2 was detected in the myxoid stroma of the choroid plexuses and in the endothelial cells in fetuses. The complete absence of the ACE2 marker was detected in epithelial cells, neurons and glial cells of the cerebral cortex, both in fetuses and in adults. Whereas a  strong but selective reactivity for ACE2 was also detected in adult choroid plexuses, mainly localized in the endothelial cells of the choroid capillaries. CONCLUSIONS: Our study shows a strong expression of ACE in the fetal and adult brain choroid plexuses. This new histopathological finding may clarify the susceptibility of the human brain to SARS-COV-2 infection. Our data indicate the choroid plexus as the entry gate of virus for in the human brain; therefore, the entrance of SARS-CoV-2 into the cerebrospinal fluid through the choroid plexuses might represent the mechanism utilized by this coronavirus to cause direct injury to brain cells.

Ultrastructural findings of lung injury due to Vaccine-induced Immune Thrombotic Thrombo- cytopenia (VITT) following COVID-19 vaccination: a scanning electron microscopic study.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare new syndrome occurring after the ChAdOx1 nCoV-19 vaccine immunization. Patients with VITT are characterized by a variable clinical presentation, likewise also the outcome of these patients is very variable. Here we report the lung ultrastructural findings in the course of VITT of a 58-year-old male patient. Alveoli were mainly dilated, irregular in shape, and occupied by a reticular network of fibrin, while interalveolar septa appeared thickened. The proliferation of small capillaries gave rise to plexiform structures and pulmonary capillary hemangiomatosis-like features. Near the alveoli occupied by a dense fibrin network, the medium-sized arteries showed a modified wall and an intraluminal thrombus. This scenario looks quite similar to that found during COVID-19, where the lungs suffer from the attack of the antigen-antibodies complexes and the virus respectively. In both diseases, the final outcome is a severe inflammation, activation of the haemostatic system and fibrinolysis.

Scanning electron microscopy of lung disease due to COVID-19-a case report and a review of the literature

OBJECTIVE: The ongoing Coronavirus pandemic (COVID-19) showed similar characteristics with the severe acute respiratory syndrome (SARS). In the most compromised cases, COVID-19 infection leads to death due to severe respiratory complications. COVID-19-related acute respiratory distress syndrome (ARDS) is the primary cause of death in these patients. In the present study, we show an ultrastructural analysis on the lungs of a patient affected by COVID-19. PATIENTS AND METHODS: Lung specimens obtained at autopsy from a 63-years old patient affected by COVID-19 were fixed in 1% paraformaldehyde. Slices of 300 mu m thickness were dehydrated and dried by Critical Point Drying in CO2. Slices were covered with a conductive gold film approximately 30 nm thick and observed at a Zeiss Sigma 300 SEM FEG in the secondary electron (SE) and backscattered electron (BSE) modes. As case control a lung biopsy from a 60-year-old man was considered. RESULTS: At low power in all COVID-19 lung specimens severe changes in the pulmonary architecture were found, due to the collapse of air spaces. Moreover, alveolar cavities were covered by large membranes. At high power, alveolar membranes showed a fibrillar structure, suggestive of a loose network of fibrin. It has been also found that intra-alveolar red blood cells were frequently present in the alveolar spaces, surrounded by a reticular fibrin network, suggestive for fibrin-hemorrhagic alveolitis. Alveolar changes were constantly associated with pathological features related to the pulmonary vessels. Vascular changes were prominent, including endothelial damage and thrombosis of large pulmonary vessels. Fibrinous microthrombi were frequently detected in the inter-alveolar septal capillaries. In addition, it has been frequently detected capillary proliferation in the alveolar septa with finding suggestive for intussusceptive neo-angiogenesis. CONCLUSIONS: In conclusion, our electron microscopy analysis showed that COVID-19-related lung disease is characterized by a substantial architectural distortion, with the interactions between alveolar and vascular changes. Intra-alveolar hyaline membranes are associated with macro-and micro-thrombotic angiopathy, ending with capillary proliferation. The new blood vessel formation originates from the septa and extends into the surrounding parenchyma. Our findings confirm previous reports on the specificity of the multiple and complex morphological pattern typical, and apparently specific, of COVID-19-related lung disease.

Aortic vulnerability to COVID-19: is the microvasculature of vasa vasorum a key factor? A case report and a review of the literature.

Arterial thromboembolic complications reported in patients with COVID-19 infection suggested that SARS-CoV-2 can trigger atherosclerotic plaque vulnerability. While endothelial cells in healthy subjects protect against thrombus formation, after injury they show prothrombotic activity. In addition, it has been hypothesized that "cytokine storm" might stimulate the production of neo-platelets triggering an abnormal "immunothrombosis" responsible for the hypercoagulable state induced in COVID-19 patients. The aim of this study is to report a case of severe COVID-19 infection characterized by the occurrence of microthrombosis in the vasa vasorum of the aorta. A 67-year-old male patient, in good health status and without comorbidities, who underwent a severe COVID-19 infection with fatal outcome, showed scattered aortic atherosclerotic plaques, characterized by multiple occlusive micro-thromboses in the vasa vasorum, spread out lymphocytic infiltrates and foci of endotheliitis and endothelial detachment. This case report confirms the previously described thrombotic involvement of vasa vasorum in COVID-19. The occurrence of the synchronous damage involving both the lumen surface (endothelial dysfunction, endotheliitis and endothelial detachment) and the adventitia (inflammation and occlusive thrombosis of vasa vasorum) could be the key points related to the fatal outcome of the SARS-CoV-2 patients. In our opinion, vasa vasorum thrombosis may thus initiate an atherogenic process that could be characterized by a much more rapid development.

Thrombotic sinusoiditis and local diffuse intrasinusoidal coagulation in the liver of subjects affected by COVID-19: the evidence from histology and scanning electron microscopy.

OBJECTIVE: Liver injury has been reported in patients with COVID-19. This condition is characterized by severe outcome and could be related with the ability of SARS-CoV-2 to activate cytotoxic T cells. The purpose of this study is to show the histological and scanning electron microscopy features of liver involvement in COVID-19 to characterize the liver changes caused by the activation of multiple molecular pathways following this infection. PATIENTS AND METHODS: Liver biopsies from 4 patients (3 post-mortems and 1 in vivo) with COVID-19 were analyzed with histology and by scanning electron microscopy. RESULTS: The liver changes showed significant heterogeneity. The first case showed ground glass hepatocytes and scattered fibrin aggregates in the sinusoidal lumen. The second evidenced intra-sinusoidal thrombi. The third was characterized by sinusoidal dilatation, atrophy of hepatocytes, Disse's spaces dilatation and intra-sinusoidal aggregates of fibrin and red blood cells. The fourth case exhibited diffuse fibrin aggregates in the dilated Disse spaces and microthrombi in the sinusoidal lumen. CONCLUSIONS: In COVID-19-related liver injury, a large spectrum of pathological changes was observed. The most peculiar features were very mild inflammation, intra-sinusoidal changes, including sinusoidal dilatation, thrombotic sinusoiditis and diffuse intra-sinusoidal fibrin deposition. These findings suggested that a thrombotic sinusoiditis followed by a local diffuse intra-vascular (intra-sinusoidal) coagulation could be the typical features of the SARS-CoV-2-related liver injury.

Vaccine-induced severe thrombotic thrombocytopenia following COVID-19 vaccination: a report of an autoptic case and review of the literature.

OBJECTIVE: Vaccine-induced immune thrombocytopenia (VITT) is a new syndrome occurring primarily in healthy young adults, with a female predominance, after receiving the first dose of ChAdOx1 nCoV-19 vaccine. We describe VITT syndrome characterized by severe thrombosis and thrombocytopenia found in our patient, with fatal outcome. CASE REPORT: A 58-year-old man, after 13 days from the first administration of ChAdOx1 nCoV-19 vaccine (AstraZeneca), presented with abdominal pain, diarrhea and vomitus. Laboratory tests revealed a severe thrombocytopenia, low fibrinogen serum levels and marked increase of D-dimer serum levels. The patient quickly developed a multiple organ failure, till death, three days after the hospital admission. RESULTS: At histology, in the lungs, interalveolar septa appeared thickened with microthrombi in the capillaries and veins. Interalveolar septa appeared thickened and showed vascular proliferation. Thrombi were detected in the capillaries of glomerular tufts. In the hearth, thrombi were observed in veins and capillaries. In the liver, voluminous fibrin thrombi were diffusely observed in the branches of the portal vein. Microthrombi were also found in the vasa vasorum of the wall of abdominal aorta. In the brain, microthrombi were observed in the capillaries of the choroid plexuses. Diffuse hemorrhagic necrosis was observed in the intestinal wall with marked congestion of the venous vessels. CONCLUSIONS: In our patient, the majority of data necessary for a VITT final diagnosis were present: thrombocytopenia and thrombosis in pulmonary, portal, hepatic, renal and mesenteric veins, associated with a marked increase of D-dimer serum levels. The finding of cerebral thrombosis in choroid plexuses, is a new finding in VITT. These features are suggestive for a very aggressive form of VITT.

Infectious agents including COVID-19 and the involvement of blood coagulation and fibrinolysis. A narrative review.

OBJECTIVE: Platelets, blood coagulation along with fibrinolysis are greatly involved in the pathophysiology of infectious diseases induced by bacteria, parasites and virus. This phenomenon is not surprising since both the innate immunity and the hemostatic systems are two ancestral mechanisms which closely cooperate favoring host's defense against foreign invaders. However, the excessive response of these systems may be dangerous for the host itself. MATERIALS AND METHODS: We searched and retrieved the articles, using the following electronic database: MedLine and Embase. We limited our search to articles published in English, but no restrictions in terms of article type, publication year, and geography were adopted. RESULTS: The hemostatic phenotype of the infectious diseases is variable depending on the points of attack of the different involved pathogens. Infectious diseases which show a prothrombotic phenotype are bacterial sepsis, SARS-CoV-2 and malaria. However, among the bacterial sepsis, Yersinia Pestis is characterized by a profibrinolytic behavior. On the contrary, the hemorrhagic fevers, due to Dengue and Ebola virus, mainly exploit the activation of fibrinolysis secondary to a huge endothelial damage which can release a large amount of t-PA in the early phase of the diseases. CONCLUSIONS: Blood coagulation and fibrinolysis are greatly activated based on the strategy of the different infectious agents which exploit the excess of response of both systems to achieve the greatest possible virulence.

Co-infection of Streptococcus pneumoniae in Respiratory Infections Caused by SARS-CoV-2

Viral respiratory infections are often associated with bacterial co-infections that often lead to increased severity and mortality of the disease. During the recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), hospitalized patients reported developing secondary bacterial infections ranging from 0 to 40% of the cases. In the previous influenza pandemics, Streptococcus pneumoniae was the most isolated bacterial pathogen causing increased mortality in patients affected by viral pneumonia. Due to the difficulty to detect pneumococcal infection in SARS-CoV-2 patients by a rapid clinical test, the real prevalence of S. pneumoniae might be underestimated, and only a few cases have been documented so far. It has been estimated that 90% of patients admitted to the Intensive Care Unit are empirically treated with antimicrobial. The application of more rapid and sensitive diagnostic methods could help with targeted antibiotic therapy. Additionally, pneumococcal vaccination of high-risk individuals could reduce bacterial pneumonia, hospital admissions, and comorbidities associated with serious illness.

COVID-19 case fatality ratio of Latino America countries with temperate climate partially follows european and oceania trends according to seasonal change

The objective of our study is, therefore, to verify whether the trend of the pandemic regarding the lethality of the virus is similar in Argentina and Chile to that which emerged in the temperate countries of Europe and Oceania. The CFRs were derived from the John Hopkins University database. To check the trend of the Case Fatality Ratio and Argentina, Chile we calculated this index on the same dates in which it was calculated for comparison in European countries and in Australia and New Zealand: i.e., May 6th and from May 6th to the September 21st. We continued comparing the other countries of the southern hemisphere, recalculating the CFR as of 11th November. For comparing a period of year homogeneous, late spring, we calculate the change if CFR from 20th March to 15th April in the North Hemisphere. Our study's results seem to confirm in Latin America a possible influence of the climate and the changing of the seasons in the lethality of the virus. For the same exceptions, it is evident that the study shows that this factor is not the only one nor probably the most important. The obvious exception concerns Argentina, which does not show any summer improvement of the CFR, unfortunately;for this, nation-specific data are not available to verify if the trend is homogeneous in the different climates that the vast territory presents. Other very important factors come into play, among which the diffusivity of the virus also seems to play a role. © 2020 by the authors.

The Climate in the European Union and the Enlarged European Region is a Determinant of the COVID-19 Case Fatality Ratio

Climate could influence the COVID-19 pandemic, but while no evidence has been advanced on the influence of colder climates, some studies have provided data to support a possible heat-related protective factor. The objective is to verify whether areas with a Cold Temperate Climate (TC) have a higher Case Fatality Ratio (CFR) for COVID-19 than areas with a Cold Climate (CC) or with a Mediterranean Climate (MC) in the European Union and the Enlarged European Region. Countries or regions were subdivided into 3 groups according to the Koppen climate classification system: TC (Cfa, Cfb and Cfc in the Koppen system);MC (Csa, Csb);CC (D and E in the Koppen system). The total number of cases and the total number of deaths were detected on 13 August 2020 on the COVID-19 Map-Johns Hopkins Coronavirus Resource Center-the CFR was thus calculated by area. Living in TC areas is strongly associated with risk of a high Case Fatality Ratio for COVID-19, OR for MC=0.42, IC 95% 0.41-0.43;OR for CC=0.33, IC 95% 0.33-0.35. The results are confirmed in the EU, OR per MC=0.85, CI 95% 0.84-0.87;OR per CC=0.63, IC 95% 0.61-0.65.The study found that the IC in a humid temperate climate is associated with higher CFR with respect to the coldest and warmest temperate climates in Europe. This does not appear to be the only determinant of the pandemic.

Is the inversion in the trend of the lethality of the covid-19 in the two hemispheres due to the difference in seasons and weather?

The climate has an influence on the COVID-19 virus lethality. The aim of this study is to verify if the summer weather coincided with the decrease of the Case Fatality Ratio (CFR) in Europe and if, on the contrary, an inverse trend was observed in Australia and New Zealand. To verify our hypothesis, we considered the largest European countries (Germany, UK, France, Italy, and Spain), plus Belgium and the Netherlands. Furthermore, we compared these countries with Australia and New Zealand. For each country considered, we have calculated the CFR from the beginning of the pandemic to May 6th and from May 6th to September 21st (late summer in Europe, late winter in the southern hemisphere). The CFRs were calculated from the John Hopkins University database. According to the results, in all European countries, a progressive decrease in CFR is observed. A diametrically opposite result is found in Australia where, on the contrary, the CFR is much higher at the end of September (at the end of winter) than on May 6th (mid-autumn), and the risk of dying if we count the infection is higher in September. In New Zealand, there are no statistically significant differences between the two surveys. The present study was based on public access macro data. © 2020 by the authors.

Association between the spread of COVID-19 and weather-climatic parameters.

OBJECTIVE: To explore whether the climate has played a role in the COVID-19 outbreak, we compared virus lethality in countries closer to the Equator with others. Lethality in European territories and in territories of some nations with a non-temperate climate was also compared. MATERIALS AND METHODS: Lethality was calculated as the rate of deaths in a determinate moment from the outbreak of the pandemic out of the total of identified positives for COVID-19 in a given area/nation, based on the COVID-John Hopkins University website. Lethality of countries located within the 5th parallels North/South on 6 April and 6 May 2020, was compared with that of all the other countries. Lethality in the European areas of The Netherlands, France and the United Kingdom was also compared to the territories of the same nations in areas with a non-temperate climate. RESULTS: A lower lethality rate of COVID-19 was found in Equatorial countries both on April 6 (OR=0.72 CI 95% 0.66-0.80) and on May 6 (OR=0.48, CI 95% 0.47-0.51), with a strengthening over time of the protective effect. A trend of higher risk in European vs. non-temperate areas was found on April 6, but a clear difference was evident one month later: France (OR=0.13, CI 95% 0.10-0.18), The Netherlands (OR=0.5, CI 95% 0.3-0.9) and the UK (OR=0.2, CI 95% 0.01-0.51). This result does not seem to be totally related to the differences in age distribution of different sites. CONCLUSIONS: The study does not seem to exclude that the lethality of COVID-19 may be climate sensitive. Future studies will have to confirm these clues, due to potential confounding factors, such as pollution, population age, and exposure to malaria.